U.S. patent application number 12/418803 was filed with the patent office on 2009-08-20 for process for preparation of 4-amino-1-isobutyl-1h-imidazo[4,5-c]-quinoline (imiquimod).
Invention is credited to Sachin Baban Gavhane, Anil Purushottam Joshi, Suresh Mahadev Kadam, Venkatasubramanian Radhakrishnan Tarur.
Application Number | 20090209764 12/418803 |
Document ID | / |
Family ID | 34978938 |
Filed Date | 2009-08-20 |
United States Patent
Application |
20090209764 |
Kind Code |
A1 |
Tarur; Venkatasubramanian
Radhakrishnan ; et al. |
August 20, 2009 |
Process for Preparation of
4-amino-1-isobutyl-1H-Imidazo[4,5-C]-quinoline (Imiquimod)
Abstract
A process for the preparation of imiquimod comprising oxidation
of 1-Isobutyl-1H-imidazo quinoline quinoline (II) afforded
1-Isobutyl-1H-imidazo-[4,5-c]-quinoline-5-N-oxide (III) which is
isolated in pure form as its hydrochloride salt (IV) followed by
conversion to 4-chloro derivative (V) and conversion to
corresponding 4-iodo derivative (VI) which is a new intermediate.
This new intermediate in convened to imiquimod (VIII) and purified
via its novel maleate salt.
Inventors: |
Tarur; Venkatasubramanian
Radhakrishnan; (Maharashtra, IN) ; Kadam; Suresh
Mahadev; (Maharashtra, IN) ; Joshi; Anil
Purushottam; (Maharashtra, IN) ; Gavhane; Sachin
Baban; (Maharashtra, IN) |
Correspondence
Address: |
PHARMACEUTICAL PATENT ATTORNEYS, LLC
55 MADISON AVENUE, 4TH FLOOR
MORRISTOWN
NJ
07960-7397
US
|
Family ID: |
34978938 |
Appl. No.: |
12/418803 |
Filed: |
April 6, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11575927 |
Mar 23, 2007 |
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PCT/IN2004/000411 |
Dec 27, 2004 |
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12418803 |
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Current U.S.
Class: |
546/82 |
Current CPC
Class: |
C07D 471/04
20130101 |
Class at
Publication: |
546/82 |
International
Class: |
C07D 471/04 20060101
C07D471/04 |
Claims
1-21. (canceled)
22. A compound selected from the group consisting of:
4-iodo-1-isobutyl-1H-imidazo[4,5-c]quinoline; and
4-amino-1-isobutyl-1H-imidazo[4,5-c]quinoline maleate.
23. The compound of claim 22, comprising
4-iodo-1-isobutyl-1H-imidazo[4,5-c]quinoline.
24. The compound of claim 22, said compound comprising
4-amino-1-isobutyl-1H-imidazo[4,5-c]quinoline maleate.
25. A process comprising converting
4-iodo-1-isobutyl-1H-imidazo[4,5-c]quinoline into imiquimod.
26. The process of claim 25, comprising converting said
4-iodo-1-isobutyl-1H-imidazo[4,5-c]quinoline into
4-amino-1-isobutyl-1H-imidazo[4,5-c]quinoline maleate, and then
converting said 4-amino-1-isobutyl-1H-imidazo[4,5-c]quinoline
maleate into imiquimod.
Description
TECHNICAL FIELD OF THE INVENTION
[0001] The present invention relates to a process for synthesis of
4-Amino-1-isobutyl-1H-imidazo[4,5-c]-quinoline. The invention also
relates to a novel purification method via a novel maleate
salt.
BACKGROUND OF THE INVENTION
[0002] Imiquimod, 4-Amino-1-isobutyl-1H-imidazo-[4,5-c]-quinoline
(VIII) is an immune response modifier, useful for treating viral
infections such as genital warts. Imiquimod is disclosed in U.S.
Pat. Nos. 4,689,338 and 5,238,944 and has the structure (VIII).
##STR00001##
[0003] Several methods are known in the prior art for making
Imiquimod (VIII).
[0004] The process of converting
1-Isobutyl-1H-imidazo-[4,5-c]-quinoline (II) to
1-Isobutyl-1H-imidazo-[4,5-c]-quinoline-5-N-oxide (III) has been
disclosed in WO 2004/0011462 A1, WO 2004/009593 A1 using peracetic
acid in toluene as a solvent. This conversion is also reported in
WO 92/15581, WO 9206093 and U.S. Pat. No. 5,175,296 using a
combination of formic acid and peracetic acid. However, since the
yields are poor and reaction being incomplete there is a need to
develop an oxidation process with milder conditions.
[0005] Reported prior arts describe various methods for the
preparation of 4-Amino-1-isobutyl-1H-imidazo[4,5-c]quinoline (VIII)
i.e. Imiquimod wherein the Introduction of amino function in the
4-position is described in three ways. Nucleophilic substitution of
a leaving group e.g. Cl or triflate with ammonia, dibenzylamine or
an azido group is the first method. The second, is by reacting
1-Isobutyl-1H-imidazo-[4,5-c]-quinoline-5-N-oxide (III) with
ammonium hydroxide or its salts in presence of tosylchloride at
0-5.degree. C. The third reported method is by reacting
1-Isobutyl-1H-imidazo-[4,5-c]-quinoline-5-N-oxide with benzoyl
isocyanate.
[0006] Patents WO 2004/009593, WO 92/06093 and U.S. Pat. Nos.
5,395,937; 5,756,747; 4,988,815; 5,602256; 5,578,727; 4,698,348;
4,689,388 as well as European patents EP 145340, EP 0385630, EP
310950 and JP 04193866 and examples therein, describe nucleophillic
substitution reactions.
[0007] In WO 97/48704 the amino group is introduced by reaction of
a 4-Chloro derivative with Sodium azide to obtain a tetrazole
moiety. Treatment of the tetrazole moiety with triphenyl phosphine
gives the 4-amino derivative.
[0008] In U.S. Pat. No. 5,395,937 a 4-triflate derivative reacts
with dibenzylamine to give 4-dibenzylamino derivative. Subsequent
catalytic reduction gives the desired amino function in
4-position.
[0009] U.S. Pat. No. 5,756,747 discloses the nucleophilic
substitution with ammonia on the corresponding 4-chloro derivative,
which is prepared by isomerization of
1-Isobutyl-1H-imidazo-[4,5-c]-quinoline-5-N-oxide (III) via the
4-hydroxy derivative followed by reaction with POCl.sub.3. Several
patents disclose nucleophilic substitution of
4-Chloro-1-isobutyl-1H-imidazo-[4,5-c]-quinoline (V) with ammonia
at high temperature and high pressure. These include U.S. Pat. No.
4,988,815; U.S. Pat. No. 5,602,256; U.S. Pat. No. 5,578,727; U.S.
Pat. No. 4,698,348; U.S. Pat. No. 4,689,388; EP 145340; EP 0385630;
EP 310950 and JP 04193866.
[0010] The patents WO 2004/009593, US2004138459, disclose a process
for the preparation of
4-Amino-1-isobutyl-1H-imidazo-[4,5-c]-quinoline (VIII) (i.e.
Imiquimod) by introducing an amino group in the 4-position via
1-Isobutyl-1H-imidazo-[4,5-c]-quinoline-4-phthalimide intermediate
(i.e. phthalimido protecting group).
[0011] WO 92/06093 discloses reaction of
1-Isobutyl-1H-imidazo-[4,5-c]-quinoline-5-N-oxide (III) with
ammonium hydroxide or ammonium salts in the presence of tosyl
chloride at 0 to 5.degree. C. to give Imiquimod.
[0012] WO 92/15581 relates to reaction of
1-Isobutyl-1H-imidazo-[4,5-c]-quinoline-5-N-oxide (III) with
benzoyl isocyanate which on subsequent hydrolysis yields Imiquimod
(VIII).
[0013] Purification of Imiquimod has been described via formation
of pharmaceutical salts in WO 2004/009593, U.S. Pat. No. 4,689,338
i.e. using HCl, H.sub.2SO.sub.4, H.sub.3PO.sub.4, HNO.sub.3 and
Methane sulfonic acid. There is still a need for preparation of
4-Amino-1-isobutyl-1H-imidazo-[4,5-c]-quinoline (VIII) namely
Imiquimod in high yield and purity.
OBJECTIVES
[0014] An object of the present invention is to develop a simple
process for the preparation of Imiquimod.
[0015] Another object of the present invention is to provide a
purification process, which is simple and implemented on a large
scale.
[0016] Further object of the present invention is to produce
Imiquimod (VIII) of high purity.
SUMMARY OF THE INVENTION
[0017] The present invention provides a process for preparing
4-Amino-1-isobutyl-1H-imidazo-[4,5-c]-quinoline (VIII) comprising:
[0018] 1) Reacting 1-Isobutyl-1H-imidazo-[4,5-c]-quinoline (II)
with per acids preferably meta-chloro perbenzoic acid in organic
solvent substantially affording cleaner
1-Isobutyl-1H-imidazo-[4,5-c]-quinoline-5-N-oxide (III). This is
further purified as its hydrochloric salt (IV). [0019] 2)
Conversion of 5-N-oxide hydrochloride (IV) to the 4-chloro
derivative (V) by treating with phosphorous oxychloride. [0020] 3)
In another aspect of the present invention is directed to a process
for preparing 4-amino-1H-imidazo-[4,5-c]-quinoline (VIII) by
reacting a compound of [4-Chloro-1H-imidazo-[4,5-c]-quinoline (V)]
with an alkali halide preferably sodium iodide to produce the
corresponding 4-iodo derivative (VI) which is converted to (VIII)
by treatment with ammonia. [0021] 4) Isolating the product VIII as
a pharmaceutically acceptable maleate salt (VII). [0022] 5) Finally
converting the Imiquimod maleate (VII) to Imiquimod (VIII) in
methanolic ammonia having purity greater than 99.5% by HPLC.
[0023] These and other aspects of the present invention will now be
described in more detail with reference to the following detailed
description of the invention.
DETAILED DESCRIPTION OF INVENTION
[0024] The present invention relates to a process for preparing
Imiquimod, 4-Amino-1-isobutyl-1H-imidazo-[4,5-c]-quinoline of
formula (VIII). However, the inventive process can be used to
prepare any compound within the scope of formula (VIII) and its
derivative including those disclosed in U.S. Pat. Nos. 5,756,747;
5,395,937; 4,689,338; EP 385630, WO 97/48704; WO 92/06093 and WO
92/15581 all of which are incorporated by reference in their
entirety.
[0025] The cyclisation of 3-Amino-4-(isobutylamino)-quinoline (I)
is accomplished by treating it with formic acid to obtain
1-isobutyl-1H-imidazo-[4,5-c]-quinoline (II). Satisfactory yield by
any method known in the art including those disclosed in patents WO
92/06093 and U.S. Pat. No. 5,175,296 all of which are incorporated
by reference in their entirety.
[0026] The 4-Iodo-1-isobutyl-1H-imidazo-[4,5-c]-quinoline i.e. (VI)
is prepared by reaction of
4-Chloro-1-isobutyl-1H-imidazo-[4,5-c]-quinoline (V) with alkali
halide such as Sodium iodide.
[0027] The 1-Isobutyl-1H-imidazo-[4,5-c]-quinoline-5-N-oxide of
formula (III) can be obtained by any method known in the art
including those in U.S. Pat. No. 5,756,747; WO 92/06093 and WO
92/15581 all of which are incorporated by reference in their
entirety. Here it has been achieved using meta-chloroperbenzoic
acid. A preferred solvent is an aliphatic alkyl ester where in
carbon chain may be preferably C.sub.1-C.sub.4. Preferably Ethyl
acetate is used as solvent. The reaction is preferably carried out
at a temperature of between 20 to 80.degree. C. more preferably
between 40 to 80.degree. C. and most preferably at about 70.degree.
C. The meta-chloroperbenzoic acid is preferably added over a period
of about 1 to 3 hrs more preferably from about 1 to 2 hrs and most
preferably for about 1 hr and 30 min. The reaction is complete when
no 1-Isobutyl-1H-imidazo-[4,5-c]-quinoline (II) is detected by TLC.
When the reaction is complete this excess of m-chloro benzoic acid
is filtered and the organic layer containing the
1H-Imidazo-[4,5-c]-quinoline-5-N-oxide (III) compound is washed
with ethyl acetate and further concentrated. This reaction is very
clean and gives higher yields in comparison to reported reference
disclosed in patent WO 2004/011462 A1, WO 2004/009593 A1, WO
92/15581, WO 9206093, U.S. Pat. No. 5,175,296.
[0028] The 1-Isobutyl-1H-imidazo-[4,5-c]-quinoline-5-N-oxide (III)
is purified by preparing its hydrochloride salt (IV) in 8%
alcoholic hydrochloride solution. A preferred alcohol is from C1-C4
aliphatic alcohol. Most preferably ethanol is used.
[0029] The hydrochloride formation is carried out at a temperature
between 5 to 20.degree. C., more preferably between 10 to
20.degree. C. and most preferably between 10 to 15.degree. C. When
the hydrochloride formation is complete the product (IV) is
filtered and washed with ethyl alcohol.
[0030] The 4-Chloro-1H-imidazo-[4,5-c]-quinoline an intermediate of
formula (V) is obtained by reaction of
1H-imidazo-[4,5-c]-quinoline-5-N-oxide hydrochloride of formula
(IV) with phosphorous oxychloride in an aprotic solvent i.e.
dimethylformamide by any method known in the art including those
disclosed in US patent U.S. Pat. No. 4,689,338 all of which are
incorporated by reference in their entirety herein.
[0031] The 4-Iodo-1H-imidazo-[4,5-c]-quinoline (VI), a novel
intermediate is prepared by reacting
4-Chloro-1H-imidazo-[4,5-c]-quinoline-(V) in an aliphatic ketone
preferably alkali halide via the halogen exchange reaction. The
reaction is preferably carried out in the presence of sodium
iodide. The reaction is achieved in acetone as a solvent. The
reaction is preferably carried out at temperatures between 25 to
35.degree. C. over a period of about 8-10 hrs. This novel compound
is characterized by its M.P., .sup.1H NMR and mass
spectroscopy.
[0032] In the penultimate stage,
4-Iodo-1H-imidazo-[4,5-c]-quinoline (VI) is converted to Imiquimod
(Crude), which is purified via its maleate salt (VII) to provide a
compound of invention of formula (VIII). The reaction is carried
out in the presence of ammonium hydroxide or preferably
ammonia.
[0033] Imiquimod (Crude) is subsequently converted to its
pharmaceutically acceptable maleate salt (VII) in aqueous alcohol.
The reaction is carried out in aliphatic alcohol and most
preferably in methanol. The proportion of alcohol:water is 2:1. The
salt formation is preferably done at 60 to 90.degree. C.
##STR00002## ##STR00003##
[0034] Maleate formation is completed in 2 to 3 hrs and then
reaction mass is cooled slowly to 25 to 35.degree. C., at this
point Imiquimod maleate (VII) crystallizes out. The product is
isolated by filtration. Imiquimod maleate (VII) is obtained in good
yield (.about.90%) and purity (99% by HPLC). Imiquimod maleate salt
(VII) is taken preferably in a mixture of water, methanol and
liquor ammonia. The reaction mass is preferably heated to 60 to
80.degree. C. more preferably at 70.degree. C. for neutralization
of salt. At an alkaline pH (.about.9-11) pale white Imiquimod
(VIII) precipitates out. The reaction mass is cooled initially to
25 to 30.degree. C. and finally cooled to 8 to 10.degree. C.
wherein pure Imiquimod precipitates out. The purity of product
enhances from 99 to 99.5% by HPLC.
EXPERIMENTAL DATA
Example No. 1
Preparation of 1-Isobutyl-1H-imidazo-[4,5-c]-quinoline (II)
[0035] 3-Amino-4-isobutyl amino quinoline (215 gm, 1.0 mole) was
dissolved in formic acid (1000 ml) and further refluxed the
reaction mass to 110-115.degree. C. Reflux was maintained for 8-10
hrs. After completion of reaction excess formic acid was removed
under reduced pressure and 3.5 L of water was added to the
concentrated mass. This diluted mass was then basified with 30%
NaOH to pH (10 to 11) at 20.degree. C. The reaction mass was
further cooled to 10.degree. C. and stirred for further 3 hrs to
obtain solid. The solid was filtered, washed with water and dried
to get the title compound (221 am, 98%) as a white solid.
TABLE-US-00001 M.P. 91 to 94.degree. C. MS-(m/z) M.sup.+ 226
.sup.1HNMR (200 MHz, DMSO D.sub.6) .delta. Values Proton 0.95 (6 H,
d, CH.sub.3 .times. 2) 2.1-2.2 (1 H, m, --CH) 4.5 (2 H, d,
CH.sub.2) 7.7 (2 H, m, Ar) 8.2-8.3 (2 H, m, Ar) 8.4 ##STR00004##
9.25 (1 H, s, --CH.dbd.N--)
Example No. 2
Preparation of
1-Isobutyl-1H-imidazo-[4,5-c]-quinoline-5-N-oxide.HCl (IV)
[0036] The compound from Example 1 (220 gm, 0.978 moles) was added
to ethyl acetate (1760 ml). The reaction mass was heated to 60 to
65.degree. C. for dissolution. Added meta-chloroperbenzoic acid
(485 gm, 70%, 1.377 moles) in lots at 60-65.degree. C. over a
period of 2-3 hrs and the temperature was maintained for 6-8 hrs.
After completion of reaction, the upper aqueous layer was
separated. The lower organic layer was then concentrated under
vacuum. To this concentrated mass was added 8% ethanolic
hydrochloride (450 ml) at 10-15.degree. C. The hydrochloride salt
was precipitated which was filtered, washed with ethyl acetate and
dried to obtain the title product (255 gm, 94%).
TABLE-US-00002 M.P. 200 to 204.degree. C. MS-(m/z) M.sup.+ 241
.sup.1HNMR (200 MHz, DMSO D.sub.6) .delta. Values Proton 0.95 (6 H,
d, CH.sub.3 .times. 2) 2.2-2.5 (1 H, m, --CH) 4.6 (2 H, d,
CH.sub.2) 8.0-8.1 (2 H, m, Ar) 8.5-8.7 (2 H, m, Ar) 8.85 (1 H, s,
--CH.dbd.N--) 10.0 ##STR00005##
Example No. 3
Preparation of 4-Chloro-1-isobutyl-1H-imidazo-[4,5-c]-quinoline
(V)
[0037] The compound from Example 2 (100 gm, 0.3603 moles) and
phosphorous oxychloride (157 gm) were then added to
N,N-Dimethylformamide (600 ml) at 20.degree. C. The resulting
solution was stirred for 30 minutes at 20.degree. C. and
subsequently heated to 80.degree. C. for 2 hrs. The resulting
suspension was drowned in the 3.0 L cold water and was basified to
pH as 9 to 10 with 30% sodium hydroxide solution. The precipitated
solid was filtered, washed with water and dried to obtain the title
product (70 gm, 74%).
TABLE-US-00003 M.P. 134 to 136.degree. C. MS-(m/z) M.sup.+ 261
.sup.1HNMR (200 MHz, DMSO D.sub.6) .delta. Values Proton 0.95 (6H,
d, CH.sub.3 .times. 2) 2.17-2.2 (1H, m, --CH) 4.5 (2H, d, CH.sub.2)
7.7-7.8 (2H, m, Ar) 8.0-8.3 (2H, m, Ar) 8.5 (1H, s,
--CH.dbd.N--)
Example No. 4
Preparation of 4-Iodo-1-isobutyl-1H-Imidazo-[4,5-c]-quinoline
(VI)
[0038] The compound from Example 3 (50 gm, 0.19 mole) was added to
acetone (200 ml). Separately prepared solution of sodium iodide in
acetone (i.e. 28 gm in 200 ml acetone) was then added dropwise to
the reaction mass and maintained at 25-30.degree. C. for 8 hrs. The
precipitated sodium chloride was filtered and the acetone was
concentrated under vacuum to obtain the title product.
TABLE-US-00004 M.P. 125 to 127.degree. C. MS-(m/z) M.sup.+ 351
.sup.1HNMR (200 MHz, DMSO D.sub.6) .delta. Values Proton 0.93 (6H,
d, CH.sub.3 .times. 2) 2.1-2.7 (1H, m, --CH) 4.53-4.57 (2H, d,
NCH.sub.2) 7.75-7.8 (2H, m, Ar) 8.08-8.11 (1H, m, Ar) 8.33-8.38
(1H, m, Ar) 8.5 (1H, s, --CH.dbd.N--)
Example No. 5
Preparation of Imiquimod (Crude)
[0039] The compound from Example 4 (67 gm, 0.1903 mole) was added
to 750 ml of 15% methanolic ammonia solution in a pressure reactor
(i.e. autoclave) and heated to 150-155.degree. C. (.about.20 Kg
pressure). The reaction mass was then maintained at this
temperature, when all the product precipitates out. The
precipitated solid was filtered and washed with 50 ml methanol. The
product was dried at 55 to 60.degree. C. for 8 hrs to obtain the
title product (40 gm, 86%).
Part A
Preparation of 4-Amino-1-isobutyl-1H-Imidazo-[4,5-c]-quinoline
maleate salt (VII)
[0040] The compound from Example 5 (35 gm, 0.145 mole) was added to
mixture of 350 ml of methanol and 175 ml water. Subsequently, 35 gm
(0.3017 mole) maleic acid was added in one lot and the reaction
mass was heated to reflux temperature 74.degree. C. Charcoalised
and maintained the reaction mass for 0.5 hr. Washed the hyflo bed
with 20 ml hot methanol and filtered the hot reaction mass through
hyflo. The filtrate was then slowly cooled to RT and then to
8-10.degree. C. in 1 hr. The precipitated product was filtered and
washed with 20 ml of methanol. The product was dried at
55-60.degree. C. (47.2 gm, 91%).
TABLE-US-00005 M.P. 190 to 192.degree. C. MS-(m/z) M.sup.+ 241
.sup.1HNMR (200 MHz, DMSO D.sub.6) .delta. Values Proton 0.95 (6H,
d, CH.sub.3 .times. 2) 2.1-2.3 (1H, m, CH) 4.5 (2H, d, NCH.sub.2)
6.09 (2H, S, .dbd.C--H of maleic acid) 7.5-7.8 (3H, m, Ar) 8.1 (1H,
d, Ar) 8.5 (1H, s, --CH.dbd.N--) 8.8 (2H, brs, --NH.sub.2) D.sub.2O
exchangeable
Part B
Preparation of 4-Amino-1-isobutyl-1H-Imidazo-[4,5-c]-quinoline
(VIII)
[0041] The compound from Example 6 (47.2 gm, 0.132 mole) was added
to a mixture of 350 ml methanol and 175 ml water. The reaction mass
was heated to 75.degree. C. and 3.5 gm charcoal was further added
and maintained for 0.5 hr. Filtered the hot reaction mass through
hyflo and subsequently added 25% ammonia solution (40 ml) till
alkaline pH. Product precipitated out was filtered, washed with
water and dried to obtain the title product (31.4 gm, 89.7%).
TABLE-US-00006 M.P. 292 to 294.degree. C. MS-(m/z) M.sup.+ 241
.sup.1HNMR (200 MHz, DMSO D.sub.6) .delta. Values Proton 0.97 (6H,
d, CH.sub.3 .times. 2) 2.18-2.25 (1H, m, CH) 4.5 (2H, d, CH.sub.2)
7.5-7.72 (2H, m, Ar) 7.8-7.9 (2H, m, Ar) 8.5 (1H, s, --CH.dbd.N--)
8.8 (1H, s, NH.sub.2) D.sub.2Oexchangeable
* * * * *